This invention relates to transgenic animal models of Alzheimer's disease.
Transgenic animal models have recently become valued tools in the elucidation of human disease processes as well as in the characterization of therapeutic drugs for disease treatment. In the case of Alzheimer's disease, a disease which currently affects 3 million persons and which is predicted to increase 50% by the year 2000, a particular need for accurate animal models exists, as highlighted by several factors. First, little is known about the etiology of the disease. Although specific proteins (including the beta-amyloid precursor protein of chromosome 21, the apoliprotein E .epsilon.4 isoform of chromosome 19, and related unknown proteins recently cloned from chromosomes 1 and 14), as well as specific gene mutations (for example, specific mutations of the beta-amyloid precursor protein) have been found to be associated with certain forms of Alzheimer's disease, their roles in disease pathology are not well understood. In addition, due to the existence of disease subgroups and the disease's debilitating nature, Alzheimer's patients are difficult to diagnose or to differentiate from patients exhibiting other forms of dementia. Finally, in terms of morphological changes, beta-amyloid accumulation within the brain is generally associated with Alzheimer's disease, but the degree of beta-amyloid variation both within a patient population and as compared to age-matched control subjects is significant. Moreover, it remains controversial whether beta-amyloid accumulation is actually causal to neuronal cell loss or to the cognitive deficits characteristic of Alzheimer's disease.
The pain of Alzheimer's disease results directly from the memory loss and cognitive deficits suffered by the patient. These eventually result in the patient's loss of identity, autonomy, and freedom. As a step toward curing this disease, alleviating its symptoms, or retarding its progression, it would be desirable to develop a transgenic animal model exhibiting the main debilitating phenotype of Alzheimer's disease, that is, memory loss, expressed concomitantly with the neuropathological correlates of Alzheimer's disease, for example, beta-amyloid accumulation, increased glial reactivity, and hippocampal cell loss.